Treatment-induced evolutionary dynamics in nonmetastatic locally advanced rectal adenocarcinoma

Multi-modal treatment of non-metastatic locally advanced rectal adenocarcinoma (LARC) includes chemotherapy, radiation, and life-altering surgery. Although highly effective for local cancer control, metastatic failure remains significant and drives rectal cancer-related mortality. A consistent observation of this tri-modality treatment paradigm is that histologic response of the primary tumor to neoadjuvant treatment(s), which varies across patients, predicts overall oncologic outcome. In this chapter, we will examine this treatment response heterogeneity in the context of evolutionary dynamics. We hypothesize that improved understanding of eco-evolutionary pressures rendering small cancer cell populations vulnerable to extinction may influence treatment strategies and improve patient outcomes. Applying effective treatment(s) to cancer populations causes a "race to extinction." We explore principles of eco-evolutionary extinction in the context of these small cancer cell populations, evaluating how treatment(s) aim to eradicate the cancer populations to ultimately result in cure. In this chapter, we provide an evolutionary rationale for limiting continuous treatment(s) with the same agent or combination of agents to avoid selection of resistant cancer subpopulation phenotypes, allowing "evolutionary rescue." We draw upon evidence from nature demonstrating species extinction rarely occurring as a single event phenomenon, but rather a series of events in the slide to extinction. We posit that eradicating small cancer populations, similar to small populations in natural extinctions, will usually require a sequence of different external perturbations that produce negative, synergistic dynamics termed the "extinction vortex." By exploiting these unique extinction vulnerabilities of small cancer populations, the optimal therapeutic sequences may be informed by evolution-informed strategies for patients with LARC.